Table 5 - uploaded by Georgios Germanidis
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Background:
Hepatitis C virus infectivity and replication efficiency appears to be dependent on the lipid content and organization of the plasma membrane of the host cell, as well as of the intracellular membranous web. As there is increasing awareness of a role played by the efflux pump ABCB1 (p-glycoprotein, P-gp) in lipid homeostasis, its funct...
Citations
... Genotyping DNA was extracted from peripheral blood with a commercial DNA extraction kit (Quick-DNA Miniprep Kit, Zymo Research, product number: D3025 Irvine, CA, USA). All polymorphisms were genotyped with previously published PCR-RFLP methods (Table 1) [24][25][26][27][28]. Genotyping was validated with negative and positive controls, by omitting DNA in the reaction mix and by using independently genotyped samples from previous studies, respectively. ...
Background:
Perioperative anesthetic and/or analgesic demand present considerable variation, and part of that variation appears to be genetic in origin. Here we investigate the impact of common polymorphisms in OPRM1, COMT, SLC6A4, ABCB1, and CYP2B6 genes, on the intra-operative consumption of remifentanil and propofol, as well as the postoperative analgesic needs, in patients subjected to thyroidectomy surgery.
Methods:
We conducted a prospective cohort study with 90 patients scheduled to undergo elective thyroidectomy, under total intravenous anesthesia achieved by target control infusion (TCI) of propofol and remifentanil. Postoperative analgesics were administered by protocol and on-demand by the individual patient. Genotyping was established by PCR-RFLP methods. Genotyping data, intra-operative hemodynamics, and total consumption of remifentanil and propofol, as well as postoperative analgesic needs and pain perception, were recorded for each individual.
Results:
Patients with the ABCB1 3435TT genotype appeared to experience significantly less pain within one hour post-operatively, compared to C carriers [mean VAS (SD) = 0.86 (1.22) vs. 2.42 (1.75); p = 0.017], a finding limited to those seeking rescue analgesic treatment. Intra-operatively, homozygotes patients for the minor allele of OPRM1 A118G and CYP2B6 G516T appeared to consume less remifentanil [mean (SD) = 9.12 (1.01) vs. 13.53 (5.15), for OPRM1 118GG and A carriers] and propofol [median (range) = 14.95 (11.53, 1359.5) vs. 121.4 (1.43, 2349.4), for CYP2B6 516TT and G carriers, respectively] but the difference was not statistically significant in our sample.
Conclusions:
The ABCB1 C3435T polymorphism appears to affect the postoperative perception of surgical pain among patients with low pain threshold. The small number of minor allele homozygotes for the OPRM1 A118G and CYP2B6 G516T polymorphisms precludes a definitive conclusion regarding the inclusion of the latter in a TCI-programming algorithm, based on the results of this study.
Clinical trial registration number:
ACTRN12616001598471.
... Information pertaining to the original groups of hyperlipidemic patients and normolipidemic controls can be found in [19] and in [27]. The participants were all Greek nationals and residents of Northern Greece. ...
... The PCR mixture was then treated overnight with FokI (SibEnzyme, Academtown, Siberia, Russia) at 37 °C; the enzyme digests in presence of the C allele (sense strand) to produce 99 and 58 bp fragments, but not in presence of the G allele (sense strand) to leave the 157 fragment uncut. Genotyping data for rs2032582were retrieved from work previously accomplished in our laboratory [19,27]. ...
Adiponutrin (patatin-like phospholipase domain-containing 3; PNPLA3), encoded in humans by the PNPLA3 gene, is a protein associated with lipid droplet and endoplasmic reticulum membranes, where it is apparently involved in fatty acid redistribution between triglycerides and phospholipids. A common polymorphism of PNPLA3 (I148M, rs738409), linked to increased PNPLA3 presence on lipid droplets, is a strong genetic determinant of non-alcoholic fatty liver disease (NAFLD) and of its progression. P-glycoprotein (Pgp, MDR1, ABCB1), encoded by the ABCB1 gene, is another membrane protein implicated in lipid homeostasis and steatosis. In the past, common ABCB1 polymorphisms have been associated with the distribution of serum lipids but not with fatty acids (FA) profiles. Similarly, data on the effect of PNPLA3 I148M polymorphism on blood FAs are scarce. In this study, a gas chromatography-flame ionization detection (GC-FID) method was optimized, allowing us to analyze twenty FAs (C14: 0, C15: 0, C15: 1, C16: 0, C16: 1, C17: 0, C17: 1, C18: 0, C18: 1cis, C18: 2cis, C20: 0, C20: 1n9, C20: 2, C20: 3n6, C20: 4n6, C20: 5, C23: 0, C24: 0 C24: 1 and C22: 6) in whole blood, based on the indirect determination of the fatty acids methyl esters (FAMES), in 62 hyperlipidemic patients and 42 normolipidemic controls. FA concentrations were then compared between the different genotypes of the rs738409 and rs2032582 (ABCB1 G2677T) polymorphisms, within and between the hyperlipidemic and normolipidemic groups. The rs738409 polymorphism appears to exert a significant effect on the distribution of blood fatty acids, in a lipidemic and fatty acid saturation state-depending manner. The effect of rs2032582 was less pronounced, but the polymorphism did appear to affect the relative distribution of blood fatty acids between hyperlipidemic patients and normolipidemic controls.
... Genotyping for the ABCB1 rs2032582 and rs1045642 and the CYP2D6*3/*4/*5/*10/xN polymorphisms was accomplished on DNA isolated from peripheral blood, using previously published restriction fragment length polymorphism and long polymerase chain reaction methods. (Gbandi et al., 2016;Okubo, Murayama, Miura, Shimizu, & Yamazaki, 2012;Schur, Bjerke, Nuwayhid, & Wong, 2001;Steijns & Van Der Weide, 1998) Genotyping failed in one patient. ...
... The two ABCB1 polymorphisms were in linkage disequilibrium (D' = 0.846, r 2 = 0.660) as expected, and their respective genotype frequencies were similar to those published previously for the general population in Greece and in other Caucasian populations (Gbandi et al., 2016). The CYP2D6 *3, *4, and xN frequencies were more or less similar to those reported earlier for a Greek population (Ragia et al., 2014). ...
Objectives:
The aim of our study was to examine the association between ABCB1 polymorphisms G2677T/A (rs2032582) and C3435T (rs1045642) and common CYP2D6 variants, with the response to antipsychotic treatment of psychotic patients, in a naturalistic setting, in Greece.
Methods:
One hundred patients suffering from schizophrenia and other psychotic disorders were included in the study. Dosages were normalized to chlorpromazine equivalents. Response following 1 month of treatment was assessed as either a continuous variable, using the distribution of the corrected Positive and Negative Syndrome Scale percent change, or as a dichotomous variable defined as the number of patients scoring ≥30% from the corrected baseline Positive and Negative Syndrome Scale score. Genotyping was achieved with established polymerase chain reaction-restriction fragment length polymorphism methods.
Results:
With response treated as a continuous variable, the homozygous recessive rs2032582 genotypes (TT) who were simultaneously carriers of a loss-of-function CYP2D6 allele (*4 or *5) responded significantly worse than the rest of the patients. Comparison of genotype frequencies revealed a statistically significant association of the above combination. No significant association between chlorpromazine equivalents and the tested genotypes was detected.
Conclusion:
We have detected a possible interaction between ABCB1 and CYP2D6 in affecting response of psychotic patients to drug treatment, in a naturalistic setting.
... 27 The ABCB1 gene appears to mediate development of resistance to anticancer drugs, and polymorphisms in this gene have been associated with HCV infectivity, ulcerative colitis, in flammatory bowel disease, and therapeutic response in patients with breast and chronic myeloid leukaemia. [28][29][30][31][32][33] In-silico examinations of the potential functional significance of SNPs identified in our study indicated a CADD C score of more than 10 for eight SNPs in the ABCB4 gene that reached genome-wide significance. Similarly, the RegulomeDB score of 2 for three SNPs indicates that these SNPs might affect transcriptional factor binding. ...
Background:
Gallbladder cancer is highly lethal, with notable differences in incidence by geography and ethnic background. The aim of this study was to identify common genetic susceptibility alleles for gallbladder cancer.
Methods:
In this case-control genome-wide association study (GWAS), we did a genome-wide scan of gallbladder cancer cases and hospital visitor controls, both of Indian descent, followed by imputation across the genome. Cases were patients aged 20-80 years with microscopically confirmed primary gallbladder cancer diagnosed or treated at Tata Memorial Hospital, Mumbai, India, and enrolled in the study between Sept 12, 2010, and June 8, 2015. We only included patients who had been diagnosed less than 1 year before the date of enrolment and excluded patients with any other malignancies. We recruited visitor controls aged 20-80 years with no history of cancer visiting all departments or units of Tata Memorial Hospital during the same time period and frequency matched them to cases on the basis of age, sex, and current region of residence. We estimated association using logistic regression, adjusting for age, sex, and five eigenvectors. We recruited samples for a replication cohort from patients visiting Tata Memorial Hospital between Aug 4, 2015, and May 17, 2016, and patients visiting the Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India, between July, 2010, and May, 2015. We used the same inclusion and exclusion criteria for the replication set. We examined three of the most significant single-nucleotide polymorphisms (SNPs) in the replication cohort and did a meta-analysis of the GWAS discovery and replication sets to get combined estimates of association.
Findings:
The discovery cohort comprised 1042 gallbladder cancer cases and 1709 controls and the replication cohort contained 428 gallbladder cancer cases and 420 controls. We observed genome-wide significant associations for several markers in the chromosomal region 7q21.12 harbouring both the ABCB1 and ABCB4 genes, with the most notable SNPs after replication and meta-analysis being rs1558375 (GWAS p=3·8 × 10(-9); replication p=0·01; combined p=2·3 × 10(-10)); rs17209837 (GWAS p=2·0 × 10(-8); replication p=0·02; combined p=2·3 × 10(-9)), and rs4148808 (GWAS p=2·4 × 10(-8); replication p=0·008; combined p=2·7 × 10(-9)). Combined estimates of per-allele trend odds ratios were 1·47 (95% CI 1·30-1·66; p=2·31 × 10(-10)) for rs1558375, 1·61 (1·38-1·89; p=2·26 × 10(-9)) for rs17209837, and 1·57 (1·35-1·82; p=2·71 × 10(-9)) for rs4148808. GWAS heritability analysis suggested that common variants are associated with substantial variation in risk of gallbladder cancer (sibling relative risk 3·15 [95% CI 1·80-5·49]).
Interpretation:
To our knowledge, this study is the first report of common genetic variation conferring gallbladder cancer risk at genome-wide significance. This finding, along with in-silico and biological evidence indicating the potential functional significance of ABCB1 and ABCB4, underlines the likely importance of these hepatobiliary phospholipid transporter genes in the pathology of gallbladder cancer.
Funding:
The Tata Memorial Centre and Department of Biotechnology.
... 7 In a recently published report co-authored by some of us, the distributions of the ABCB1 3435C>T and 2677G>T/A (rs2032582) genotypes in hyperlipidemic patients were shown to deviate from the corresponding distributions in non-selected health professionals that served as controls. 8 In this study we examine the association between rs1045642 and rs2032582, and blood lipids, in the same group of hyperlipidemic patients and in normolipidemic controls, in an effort to further our understanding of the apparently complex but potentially clinically significant relationship between lipid homeostasis and ABCB1. ...
... [2][3][4][5][6] We were also able to reconfirm the previously observed overrepresentation of the ancestral homozygous genotypes of both polymorphisms in the hyperlipidemics as compared to the normolipidemics participants. 8 In the cell, the majority of cholesterol is embedded in the phospholipid bilayer of the plasma membrane, often associated with sphingomyelin (SM) in lipid rafts. 10 Mobilization of cholesterol from the plasma membrane is facilitated by the weakening of cholesterol -SM interactions brought about by a sphingomyelinasecatalyzed reaction; the former however is blocked by ABCB1 inhibitors, suggesting that ABCB1 modulates this process, as well as that of cholesterol biosynthesis, by affecting the mobilization of sterol precursors in a similar manner. ...
Background
Dyslipidemia is a predisposing factor for coronary heart disease (CHD). High-intensity statin therapy is recommended as secondary prevention. ABCB1 and SLCO1B1 genes influence the efficacy and safety of statins. Xinjiang is a multi-ethnic area; however, little is known about the prevalence of dyslipidemia and gene polymorphisms of ABCB1 and SLCO1B1 in minority groups with CHD.
Objective
To measure levels of lipid and apolipoprotein and the prevalence of dyslipidemia and gene polymorphisms of ABCB1 , SLCO1B1 in Han, Uygur, Kazak, Hui, Tatar, Kirgiz, and Sibe populations with CHD in Xinjiang.
Methods
This descriptive retrospective study compares lipid levels in ethnic groups using Kruskal-Wallis test or analysis of variance. The study compared gene polymorphisms and the prevalence of dyslipidemia among different ethnic groups using the chi-square test. The lipid profiles in plasma were measured before lipid-lowering therapy using commercially available kits. Genotyping of SLCO1B1 and ABCB1 variants was performed using sequencing by hybridization.
Results
A total of 2218 patients were successfully screened, including 1044 Han, 828 Uygur, 113 Kazak, 138 Hui, 39 Tatar, 36 Kirgiz, and 20 Sibe patients. The overall mean age was 61.8 ± 10.8 years, and 72.5% of participants were male. Dyslipidemia prevalence in these ethnic groups was 42.1, 49.8, 52.2, 40.6, 48.7, 41.7, and 45.0%, respectively. The prevalence of dyslipidemia, high total cholesterol (TC), high triglycerides (TG), and high low density lipoprotein cholesterol (LDL-C) differed significantly among the groups ( P = 0.024; P < 0.001; P < 0.001; P < 0.001, respectively). For the Han group, high LDL-C, high TC, and high TG prevalence differed significantly by gender ( P = 0.001, P = 0.022, P = 0.037, respectively). The prevalence of high TC, high TG, and low high density lipoprotein cholesterol (HDL-C) differed significantly by gender in the Uygur group ( P = 0.006, P = 0.004, P < 0.001, respectively). The prevalence of high TC in Hui patients significantly differed by gender ( P = 0.043). These findings suggest that polymorphisms in ABCB1 and C3435T differ significantly across ethnicities ( P < 0.001).
Conclusions
The prevalences of dyslipidemia, high TC, high TG, and high LDL-C in Han, Uygur, Kazak, Hui, Tatar, Kirgiz, and Sibe CHD patients in Xinjiang differed concerning ethnicity. Ethnic, gender, and lifestyle were the key factors that affected the lipid levels of the population. The prevalence of polymorphisms of ABCB1 and C3435T significantly differed across ethnicities. These findings will aid the selection of precision lipid-lowering medications and prevention and treatment of CHD according to ethnicity in Xinjiang.
